1. Field of the Invention
The present invention relates to a deliberated hypotensive agent comprising diadenosine 5', 5'"-p.sup.1,p.sup.4 -tetraphosphate or a salt thereof.
2. Discussion of Background
Since around 1940, hypotensive anesthesia has been applied in various surgeries to make surgical operations easy and to decrease surgical blood loss during surgery.
The clinical advantages of hypotensive anesthesia are that the amount of blood transfusion can be reduced, risks accompanied by blood transfused can be minimized, and surgical operation time can be decreased by producing a drier surgical field. Because of these advantages and other advantages, hypotensive anesthesia is now employed in various surgeries (Fumio Goto et al., The Japanese Journal of Anesthesiology, 2, 199, 1983).
Hypotension can be produced by various methods. For example, in early 1930s, a method of discharging a large amount of blood from the body, and spinal cord anesthesia, extradural anesthesia, halothane anesthesia, and combinations thereof will deep anesthesia were conducted. However, when blood pressure is artificially decreased by discharging blood with deep anesthesia, circulation failure of vital organs such as brain, heart and kidney, can develop (D. M. Little, Anesthesiology 16, 320, 1955; A. G. Larson, Anesthesiology, 25, 682, 1964). For this reason, trimethaphan (Trademark "Arfonad") is now used in combination with general anesthesia. Trimethaphan has excellent blood pressure regulation effect. However this effect lasts for a relatively long period of time, so that cardiac contractility, cardiac output, and coronary blood flow are decreased by the ganglionic blockade thereof and histamine liberation effect is increased. Furthermore, trimethaphan has the shortcomings that administration of a large amount of trimethaphan causes renal insufficiency because of tubular impairment near the kidney, tachyphylaxis, tachycardia, and mydriasis after its use. As a result, a significant improvement in hypotensitive anesthesia by deep anesthesia has not been attained (J. A. Agnilar and E. B. Boldrey, Anesthesiology 21, 3, 1960; A. G. Larson, Anesthesiology 25, 682, 1964; G. G. Rowe et al., Anesthesiology 25, 156, 1964).
Sodium nitroprusside and nitroglycerin were then tried. These have an excellent blood pressure regulation effect and are effective in maintaining coronary circulation accurately. Sodium nitroprusside, however, has fatal shortcomings in that it can cause histotoxic-anoxia-induced metabolic acidosis (Masaya Nakamura, Fukuoka Acta Medica 67, 514, 1976), and the cyanide contained in the compound is liberated within the body to induce cyanide poisoning (D. W. Davies et al., Canad. Anaeths. Soc. J. 22, 553, 1975; C. J. Vesey et al., Br. Med. J. 22, 140, 1974).
On the other hand, it has been pointed out that nitroglycerin has the shortcomings that congestion by the expansion of vanation, and tachycardia are caused (N. R. Fahmy, Anesthesiology 49, 17, 1978), sthenia of brain pressure is caused (S. Doli et al., Anesthesiology 54, 511, 1981), and the arterial oxygen tension (PaO.sub.2) is decreased during hypotensive anesthesia (M. D. Oliverira et al., Br. J. Anaesth. 53, 11, 1981).
For these reasons, at present, nitroglycerin or prostaglandin E.sub.1 (hereinafter referred to as PG E.sub.1) is used in combination with general anesthesia.
At present, halothane is well known as an anesthetic for general anesthesia used under hypotensive anesthesia. Halothane anesthesia exhibits only a slight inhibitory effect on the circulation, but when surgery is extended for a long period of time, it causes hepatotoxicity and sthenia of brain pressure (S. Doli et al., Anesthesiology 54, 511, 1981; Tsutomu Mitsufuji et al., Anesthesia 31, 1102, 1982). Therefore, NLA (neuroleptannalgesia) is frequently used in surgery. However, NLA also frequently causes hypertension during surgery in the same manner as in the case of halothane anesthesia, so that control of its use is important. Furthermore, when halothane anesthesia is applied, hypertension is also caused by psychological stress before and after surgery.
In contrast to the above-mentioned anesthesia, hypotensive anesthesia has the advantages that blood loss can be minimized, surgery is made easier, and the stress induced by anesthetics and surgery can be minimized.
It is required that a deliberated hypotensive agent used during anesthesia show the following performance:
1. Excellent blood pressure regulation performance. Rapid onset of action upon the initiation of the administration, adequate control of blood pressure and rapid reversibilty upon the termination of the administration can be attained. PA1 2. Production of decreased blood pressure regardless of the kind of anesthetic employed. PA1 3. No decrease in blood flow into vital organs such as heart, liver, kidney, and brain under anesthesia. PA1 4. No adverse effects on heart (i.e., no decrease in cardiac output, and no changes in heart rate and electrocardiogram). PA1 5. Without causing tachyphylaxis. PA1 6. Without causing rebound hypertension. PA1 7. Without causing tachycardia. PA1 8. Without increasing brain pressure. PA1 9. Without causing acidosis. PA1 10. Without decreasing gas tension in blood. PA1 11. Without causing serious side effects.